BackgroundThere is renewed interest in magnetic hyperthermia as a treatment modality for cancer, especially when it is combined with other more traditional therapeutic approaches, such as the co-delivery of anticancer drugs or photodynamic therapy.MethodsThe influence of bimagnetic nanoparticles (MNPs) combined with short external alternating magnetic field (AMF) exposure on the growth of subcutaneous mouse melanomas (B16-F10) was evaluated. Bimagnetic Fe/Fe3O4 core/shell nanoparticles were designed for cancer targeting after intratumoral or intravenous administration. Their inorganic center was protected against rapid biocorrosion by organic dopamine-oligoethylene glycol ligands. TCPP (4-tetracarboxyphenyl porphyrin) units were attached to the dopamine-oligoethylene glycol ligands.ResultsThe magnetic hyperthermia results obtained after intratumoral injection indicated that micromolar concentrations of iron given within the modified core-shell Fe/Fe3O4 nanoparticles caused a significant anti-tumor effect on murine B16-F10 melanoma with three short 10-minute AMF exposures. We also observed a decrease in tumor size after intravenous administration of the MNPs followed by three consecutive days of AMF exposure 24 hrs after the MNPs injection.ConclusionsThese results indicate that intratumoral administration of surface modified MNPs can attenuate mouse melanoma after AMF exposure. Moreover, we have found that after intravenous administration of micromolar concentrations, these MNPs are capable of causing an anti-tumor effect in a mouse melanoma model after only a short AMF exposure time. This is a clear improvement to state of the art.

Localized magnetic hyperthermia as a treatment modality for cancer has generated renewed interest, particularly if it can be targeted to the tumor site. We examined whether tumor-tropic neural progenitor cells (NPCs) could be utilized as cell delivery vehicles for achieving preferential accumulation of core/shell iron/iron oxide magnetic nanoparticles (MNPs) within a mouse model of melanoma. We developed aminosiloxane-porphyrin functionalized MNPs, evaluated cell viability and loading efficiency, and transplanted neural progenitor cells loaded with this cargo into mice with melanoma. NPCs were efficiently loaded with core/shell Fe/Fe 3 O 4 MNPs with minimal cytotoxicity; the MNPs accumulated as aggregates in the cytosol. The NPCs loaded with MNPs could travel to subcutaneous melanomas, and after A/C (alternating current) magnetic field (AMF) exposure, the targeted delivery of MNPs by the cells resulted in a measurable regression of the tumors. The tumor attenuation was significant (p<0.05) a short time (24 hours) after the last of three AMF exposures. Keywords nanotechnology; cell-based; targeted delivery; magnetic nanoparticles; magnetic hyperthermia; melanoma; neural progenitor cellsThe incidence and mortality rate of malignant melanoma continues to increase at an alarming rate worldwide.1 Disseminated melanoma is not curable using current clinical * Corresponding author: Deryl Troyer, Department of Anatomy and Physiology, 228 Coles Hall, Kansas State University, Manhattan, KS 66506, USA troyer@vet.ksu.edu,. ** Both of these authors contributed equally to this work. Supporting Information Available:Supplemental Figures S1 and S2 show a TEM image of MNPs and a photo of a hemacytometer grid with trypan blue-stained, MNP-loaded NPCs, respectively. The figures and accompanying legends are available This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript ACS Nano. Author manuscript; available in PMC 2011 December 28. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript tools; traditional chemotherapy is ineffective due to inherent drug-resistant characteristics of the disease.2 , 3The pioneering studies of Gordon et al. demonstrated induced intracellular hyperthermia using dextran magnetite nanoparticles in a high frequency magnetic field (such as 500 kHz); the advantages of magnetic nanoparticles (MNPs), such as negligible or low toxicity, biocompatibility, injectability into the blood stream, and potential accumulation in the target tumor, make them prime candidates for hyperthermia applications.4 However, the specific absorption rates (SARs) of those early systems were low. It will be of great importance to achieve a high monodispersity of the magnetic nanoparticles, because only then can the A/ C-excitation be optimized to achieve very high specific absorption rates. Magnetic hyperthermia has recently garnered new interest as a cancer therapy because technological advances allow heat delivery to be more precisely contro...

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Using magnetic nanoparticles to absorb alternating magnetic field energy as a method of generating localized hyperthermia has been shown to be a potential cancer treatment. This report demonstrates a system that uses tumor homing cells to actively carry iron/iron oxide nanoparticles into tumor tissue for alternating magnetic field treatment. Paramagnetic iron/ iron oxide nanoparticles were synthesized and loaded into RAW264.7 cells (mouse monocyte/ macrophage-like cells), which have been shown to be tumor homing cells. A murine model of disseminated peritoneal pancreatic cancer was then generated by intraperitoneal injection of Pan02 cells. After tumor development, monocyte/macrophage-like cells loaded with iron/ iron oxide nanoparticles were injected intraperitoneally and allowed to migrate into the tumor. Three days after injection, mice were exposed to an alternating magnetic field for 20 minutes to cause the cell-delivered nanoparticles to generate heat. This treatment regimen was repeated three times. A survival study demonstrated that this system can significantly increase survival in a murine pancreatic cancer model, with an average post-tumor insertion life expectancy increase of 31%. This system has the potential to become a useful method for specifically and actively delivering nanoparticles for local hyperthermia treatment of cancer.

SummaryThe targeted delivery of therapeutics to the tumor site is highly desirable in cancer treatment, because it is capable of minimizing collateral damage. Herein, we report the synthesis of a nanoplatform, which is composed of a 15 ± 1 nm diameter core/shell Fe/Fe3O4 magnetic nanoparticles (MNPs) and the topoisomerase I blocker SN38 bound to the surface of the MNPs via a carboxylesterase cleavable linker. This nanoplatform demonstrated high heating ability (SAR = 522 ± 40 W/g) in an AC-magnetic field. For the purpose of targeted delivery, this nanoplatform was loaded into tumor-homing double-stable RAW264.7 cells (mouse monocyte/macrophage-like cells (Mo/Ma)), which have been engineered to express intracellular carboxylesterase (InCE) upon addition of doxycycline by a Tet-On Advanced system. The nanoplatform was taken up efficiently by these tumor-homing cells. They showed low toxicity even at high nanoplatform concentration. SN38 was released successfully by switching on the Tet-On Advanced system. We have demonstrated that this nanoplatform can be potentially used for thermochemotherapy. We will be able to achieve the following goals: (1) Specifically deliver the SN38 prodrug and magnetic nanoparticles to the cancer site as the payload of tumor-homing double-stable RAW264.7 cells; (2) Release of chemotherapeutic SN38 at the cancer site by means of the self-containing Tet-On Advanced system; (3) Provide localized magnetic hyperthermia to enhance the cancer treatment, both by killing cancer cells through magnetic heating and by activating the immune system.

Fast drug delivery is very important to utilize drug molecules that are short-lived under physiological conditions. Techniques that can release model molecules under physiological conditions could play an important role to discover the pharmacokinetics of short-lived substances in the body. Here an experimental method is developed for the fast release of the liposomes' payload without a significant increase in (local) temperatures. This goal is achieved by using short magnetic pulses to disrupt the lipid bilayer of liposomes loaded with magnetic nanoparticles. The drug release has been tested by two independent assays. The first assay relies on the AC impedance measurements of MgSO4 released from the magnetic liposomes. The second standard release assay is based on the increase of the fluorescence signal from 5(6)-carboxyfluorescein dye when the dye is released from the magneto liposomes. The efficiency of drug release ranges from a few percent to up to 40% in the case of the MgSO4. The experiments also indicate that the magnetic nanoparticles generate ultrasound, which is assumed to have a role in the release of the model drugs from the magneto liposomes.

In this study, the interactions of two gold nanoparticles of different sizes (average diameters of 3.7 +/- 2.6 and 17 +/- 3 nm) with octameric mycobacterial porin A from Mycobacterium smegmatis (MspA) and a mutant of MspA featuring a cysteine mutation in position 126 (Q126C) are investigated. From the observation of enhanced photoluminescence quenching, it is inferred that the presence of eight cysteines in the MspA Q126C mutant significantly enhances the binding of selected small gold nanoparticles within the inner pore of MspA. The large gold nanoparticle/porin complex shows photoluminescence enhancement, which is expected since the larger nanoparticles cannot dock within the homopore of MspA due to size exclusion. In addition to the fluorescence experiments, observation of energy transfer from the small gold nanoparticles to the MspA shows the close proximity of the small gold nanoparticles with the porin. Interestingly, the energy transfer of the large nanoparticle/MspA complex is completely missing. From high-performance liquid chromatography data, the estimated binding constants for small Au@MspA, large Au@MspA, small Au@MspAcys, and large Au@MspAcys are 1.3 x 10 (9), 2.22 x 10 (10), > 10 (12) (irreversible), and 1.7 x 10 (10), respectively.

The octameric porin MspA from Mycobacterium smegmatis is sufficiently stable to form a nonmembrane-supported stand-alone porin on Mica surfaces. About 98% of all MspA octamers were found to stand upright on Mica, with their periplasmic loop regions bound to the hydrophilic Mica surface. Both, small (d = 3.7 nm) and large (d = 17 nm) gold nanoparticles bind to MspA, however in different positions: small gold nanoparticles bind within the MspA pore, whereas the large gold nanoparticles bind to the upper region of MspA. These experiments demonstrate that gold nanoparticles can be positioned at different, well-defined distances from the underlying surface using the MspA pore as a template. These findings represent a significant step towards the use of electrically insulating stable proteins in combination with metal nanoparticles in nanodevices.